Immunosuppressive agents are widely used in the treatment of autoimmune disease and in treating or preventing transplantation rejection, including the treatment of graft-versus-host disease (GVHD), a condition in which transplanted marrow cells attack the recipient's cells. Common immunosuppressive agents include azathioprine, corticoste-roids, cyclophosphamide, methotrexate, 6-mercaptopurine, vincristine, and cyclosporin A. In general, none of these drugs are completely effective, and most are limited by severe toxicity. For example, cyclosporin A, a widely used agent, is significantly toxic to the kidney. In addition, doses needed for effective treatment may increase the patient's susceptibility to infection by a variety of opportunistic invaders.
A number of compounds isolated from the Chinese medicinal plant Tripterygium wilfordii (TW) have been identified as having immunosuppressive activity. Representative compounds include triptolide, 16-hydroxytriptolide, triptophenolide, tripdiolide, and tripchlorolide, as described, for example, in Lipsky et al. (1994) and Zheng et al. (1991; 1994).
The administration and therapeutic effectiveness of these compounds have been limited, however, by their low water solubility. This problem has been addressed by formulating the compounds in mixtures of ethanol and polyethoxylated castor oil (e.g., "CREMOPHOR EL.TM."), allowing subsequent dilution in saline for intravenous administration. However, such formulations have suffered from high toxicity, due to the high concentration of solubilizing agent required to dissolve these compounds. For example, the ratio of solubilizing agent (ethanol plus "CREMOPHOR EL.TM.") to triptolide in such formulations is typically on the order of 1000:1 or greater, due to the poor solubility of triptolide (Morris, 1991; Morris et al., 1991). Standardization of dosage amounts is also more problematic with a suspension than with a solution.
It is therefore desirable to provide immunosuppressive compounds having comparatively low toxicity and improved water solubility. Ideally, such compounds would show immunosuppressive activity in their water soluble form, or would be convertible to an immunosuppressive form in vivo.